Radiation therapy is a major modality in the treatment of cancer. However, as the application and efficacy of this treatment has increased, so has the concern for normal tissue toxicity. For the treatment of abdominal and pelvic tumors, intestinal tolerance is often a major limiting factor. Studies from the applicants' lab and other laboratories have demonstrated dramatic changes in small intestinal and colonic motor activity following fractionated or single sub-lethal doses of ionizing radiation. Many of these changes have direct symptomatic relevance to patients receiving radiation therapy and are responsible for emesis, gastrointestinal cramping and explosive diarrhea. The applicants have correlated improvements in the contractile changes with pharmacologic interventions which improve patient tolerance. They now propose to continue the efforts, focusing on the mechanisms responsible for the changes they have observed. The primary objectives of this research proposal are 1) to explore the role of central and peripheral neurokinin 1 receptors in the contractile changes produced by irradiation, 2) to understand the mechanisms of the coordination between the small intestinal and colonic contractions induced by irradiation and 3) to define the role of the putative inhibitory neurotransmitter, nitric oxide, in the radiation induced contractions. In a canine model, contractile recordings will be made using strain gauges. They will be implanted in the animals using sterile surgical techniques. Antagonists of neurokinin 1 receptor or nitric oxide synthase inhibitors will be administered either intravenously, intracerebroventricularly or using close intraarterial techniques in conscious and neurologically intact animals. More detailed investigations will be performed in a rodent model and the results correlated with the clinically relevant model of motility changes. The ultimate aim is to delineate the mechanisms that produce abnormal motor patterns during radiation therapy in humans. With this understanding, the applicants will be able to propose appropriate pharmacologic agents to block these gastrointestinal effects and improve human tolerance to radiation exposure.